tbuckley/cabot-search huggingface dataset:
Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial
Authors: Y. Tao, J. Biau, X.S. Sun, C. Sire, L. Martin, M. Alfonsi, J.B. Prevost, A. Modesto, C. Lafond, J.M. Tourani, J. Miroir, M.C. Kaminsky, A. Coutte, X. Liem, E. Chautard, E. Vauleon, F. Drouet, A. Ruffier, J.F. Ramee, G. Waksi, A. Péchery, M. Wanneveich, J. Guigay, A. Aupérin, J. Bourhis
Journal: Annals of Oncology (2022)
Loss of long-chain acyl-CoA synthetase 1 promotes hepatocyte death in alcohol-induced steatohepatitis
Authors: Haibo Dong, Wei Zhong, Wenliang Zhang, Liuyi Hao, Wei Guo, Ruichao Yue, Xinguo Sun, Zhaoli Sun, Ramon Bataller, Zhanxiang Zhou
Journal: Metabolism (2022)
Polyamines from myeloid-derived suppressor cells promote Th17 polarization and disease progression
Authors: Cong Hu, Yu Zhen, Zhanchuan Ma, Li Zhao, Hao Wu, Chang Shu, Bo Pang, Jinyu Yu, Ying Xu, Xin Zhang, Xiang-yang Wang, Huanfa Yi
Journal: Molecular Therapy (2022)

Myeloid-derived suppressor cells (MDSCs) are a group of immature myeloid cells that play an important role in diseases. MDSCs promote Th17 differentiation and aggravate systemic lupus erythematosus (SLE) progression by producing arginase-1 to metabolize arginine. However, the metabolic regulators remain unknown. Here, we report that MDSC derivative polyamines can promote Th17 differentiation via miR-542–5p in vitro. Th17 polarization was enhanced in response to polyamine treatment or upon miR-542–5p overexpression. The TGF-β/SMAD3 pathway was shown to be involved in miR-542-5p-facilitated Th17 differentiation. Furthermore, miR-542–5p expression positively correlated with the levels of polyamine synthetases in peripheral blood mononuclear cells of patients with SLE as well as disease severity. In humanized SLE model mice, MDSC depletion decreased the levels of Th17 cells, accompanied by reduced expression of miR-542–5p and these polyamine synthetases. In addition, miR-542–5p expression positively correlated with the Th17 level and disease severity in both patients and humanized SLE mice. Together, our data reveal a novel molecular pathway by which MDSC-derived polyamine metabolism enhances Th17 differentiation and aggravates SLE. Myeloid-derived suppressor cells (MDSCs) are a group of immature myeloid cells that play an important role in diseases. MDSCs promote Th17 differentiation and aggravate systemic lupus erythematosus (SLE) progression by producing arginase-1 to metabolize arginine. However, the metabolic regulators remain unknown. Here, we report that MDSC derivative polyamines can promote Th17 differentiation via miR-542–5p in vitro. Th17 polarization was enhanced in response to polyamine treatment or upon miR-542–5p overexpression. The TGF-β/SMAD3 pathway was shown to be involved in miR-542-5p-facilitated Th17 differentiation. Furthermore, miR-542–5p expression positively correlated with the levels of polyamine synthetases in peripheral blood mononuclear cells of patients with SLE as well as disease severity. In humanized SLE model mice, MDSC depletion decreased the levels of Th17 cells, accompanied by reduced expression of miR-542–5p and these polyamine synthetases. In addition, miR-542–5p expression positively correlated with the Th17 level and disease severity in both patients and humanized SLE mice. Together, our data reveal a novel molecular pathway by which MDSC-derived polyamine metabolism enhances Th17 differentiation and aggravates SLE.
Longitudinal assessment of the health-related quality of life of children and adolescents with chronic kidney disease
Authors: Chandana Guha, Anita van Zwieten, Rabia Khalid, Siah Kim, Amanda Walker, Anna Francis, Madeleine Didsbury, Armando Teixeira-Pinto, Belinda Barton, Chanel Prestidge, Emily Lancsar, Fiona Mackie, Joseph Kwon, Kirsten Howard, Kylie-Ann Mallitt, Martin Howell, Allison Jaure, Alison Hayes, Rakhee Raghunandan, Stavros Petrou, Suncica Lah, Steven McTaggart, Jonathan C. Craig, Germaine Wong
Journal: Kidney International (2022)
Integrated genomic surveillance enables tracing of person-to-person SARS-CoV-2 transmission chains during community transmission and reveals extensive onward transmission of travel-imported infections, Germany, June to July 2021
Authors: Torsten Houwaart, Samir Belhaj, Emran Tawalbeh, Dirk Nagels, Yara Fröhlich, Patrick Finzer, Pilar Ciruela, Aurora Sabrià, Mercè Herrero, Cristina Andrés, Andrés Antón, Assia Benmoumene, Dounia Asskali, Hussein Haidar, Janina von Dahlen, Jessica Nicolai, Mygg Stiller, Jacqueline Blum, Christian Lange, Carla Adelmann, Britta Schroer, Ute Osmers, Christiane Grice, Phillipp P. Kirfel, Hassan Jomaa, Daniel Strelow, Lisanna Hülse, Moritz Pigulla, Pascal Kreuzer, Alona Tyshaieva, Jonas Weber, Tobias Wienemann, Malte Kohns Vasconcelos, Katrin Hoffmann, Nadine Lübke, Sandra Hauka, Marcel Andree, Claus Jürgen Scholz, Nathalie Jazmati, Klaus Göbels, Rainer Zotz, Klaus Pfeffer, Jörg Timm, Lutz Ehlkes, Andreas Walker, Alexander T. Dilthey
Journal: Eurosurveillance (2022)

BackgroundTracking person-to-person SARS-CoV-2 transmission in the population is important to understand the epidemiology of community transmission and may contribute to the containment of SARS-CoV-2. Neither contact tracing nor genomic surveillance alone, however, are typically sufficient to achieve this objective.AimWe demonstrate the successful application of the integrated genomic surveillance (IGS) system of the German city of Düsseldorf for tracing SARS-CoV-2 transmission chains in the population as well as detecting and investigating travel-associated SARS-CoV-2 infection clusters.MethodsGenomic surveillance, phylogenetic analysis, and structured case interviews were integrated to elucidate two genetically defined clusters of SARS-CoV-2 isolates detected by IGS in Düsseldorf in July 2021.ResultsCluster 1 (n = 67 Düsseldorf cases) and Cluster 2 (n = 36) were detected in a surveillance dataset of 518 high-quality SARS-CoV-2 genomes from Düsseldorf (53% of total cases, sampled mid-June to July 2021). Cluster 1 could be traced back to a complex pattern of transmission in nightlife venues following a putative importation by a SARS-CoV-2-infected return traveller (IP) in late June; 28 SARS-CoV-2 cases could be epidemiologically directly linked to IP. Supported by viral genome data from Spain, Cluster 2 was shown to represent multiple independent introduction events of a viral strain circulating in Catalonia and other European countries, followed by diffuse community transmission in Düsseldorf.ConclusionIGS enabled high-resolution tracing of SARS-CoV-2 transmission in an internationally connected city during community transmission and provided infection chain-level evidence of the downstream propagation of travel-imported SARS-CoV-2 cases.
Precision oncology provides opportunities for targeting KRAS-inhibitor resistance
Authors: Martin Sattler, Atish Mohanty, Prakash Kulkarni, Ravi Salgia
Journal: Trends in cancer (2022)

Novel inhibitors targeting Kirsten rat sarcoma virus homolog (KRAS) KRASG12C in various cancers have shown good initial efficacy, but therapy-related drug resistance eventually occurs in most patients. It has become apparent that cancer cells not only rely on novel mutations that provide escape mechanisms, but about half of them become resistant in the absence of apparent genetic mutations. Redundancies within the KRAS signaling pathways and cross-talk between these pathways - as well as other canonical cancer-driving mechanisms - not only provide challenges but also present opportunities for drug development and targeted approaches. We discuss the challenges for the duality of KRAS inhibitor drug resistance with an additional focus on nongenetic mechanisms and the potential for patient-centered combination treatments.
Risk Variants in the Exomes of Children With Critical Illness
Authors: Joshua E. Motelow, Natalie C. Lippa, Joseph Hostyk, Evin Feldman, Matthew Nelligan, Zhong Ren, Anna Alkelai, Joshua D. Milner, Ali G. Gharavi, Yingying Tang, David B. Goldstein, Steven G. Kernie
Journal: JAMA Network Open (2022)

Importance Diagnostic genetic testing can lead to changes in management in the pediatric intensive care unit. Genetic risk in children with critical illness but nondiagnostic exome sequencing (ES) has not been explored. Objective To assess the association between loss-of-function (LOF) variants and pediatric critical illness. Design, Setting, and Participants This genetic association study examined ES first screened for causative variants among 267 children at the Morgan Stanley Children’s Hospital of NewYork-Presbyterian, of whom 22 were otherwise healthy with viral respiratory failure; 18 deceased children with bronchiolitis from the Office of the Chief Medical Examiner of New York City, of whom 14 were previously healthy; and 9990 controls from the Institute for Genomic Medicine at Columbia University Irving Medical Center. The ES data were generated between January 1, 2015, and December 31, 2020, and analyzed between January 1, 2017, and September 2, 2022. Exposure Critical illness. Main Outcomes and Measures Odds ratios and P values for genes and gene-sets enriched for rare LOF variants and the loss-of-function observed/expected upper bound fraction (LOEUF) score at which cases have a significant enrichment. Results This study included 285 children with critical illness (median [range] age, 4.1 [0-18.9] years; 148 [52%] male) and 9990 controls. A total of 228 children (80%) did not receive a genetic diagnosis. After quality control (QC), 231 children harbored excess rare LOF variants in genes with a LOEUF score of 0.680 or less (intolerant genes) ( P = 1.0 × 10 −5 ). After QC, 176 children without a diagnosis harbored excess ultrarare LOF variants in intolerant genes but only in those without a known disease association (odds ratio, 1.8; 95% CI, 1.3-2.5). After QC, 25 children with viral respiratory failure harbored excess ultrarare LOF variants in intolerant genes but only in those without a known disease association (odds ratio, 2.8; 95% CI, 1.1-6.6). A total of 114 undiagnosed children were enriched for de novo LOF variants in genes without a known disease association (observed, 14; expected, 6.8; enrichment, 2.05). Conclusions and Relevance In this genetic association study, excess LOF variants were observed among critically ill children despite nondiagnostic ES. Variants lay in genes without a known disease association, suggesting future investigation may connect phenotypes to causative genes.
Effects of a Narrative-Based Psychoeducational Intervention to Prepare Patients for Responding to Acute Myocardial Infarction
Authors: Polly W. C. Li, Doris S. F. Yu, Bryan P. Yan, C. W. Wong, Sunny C. S. Yue, Cecilia M. C. Chan
Journal: JAMA Network Open (2022)

Importance Despite decades of educational efforts, patients’ prolonged delays in seeking care for symptoms of acute myocardial infarction (AMI) remain the greatest obstacle to successful management of the condition. Objective To compare the effects of a narrative-based psychoeducational intervention with a didactic educative approach on AMI survivors’ intention to seek care for AMI symptoms and on AMI knowledge. Design, Setting, and Participants A multisite randomized clinical trial recruited community-dwelling patients aged 18 years or older with a history of AMI from 4 hospitals in Hong Kong from January 1, 2018, to January 22, 2021, and followed up participants for 1 year. Interventions An 8-week narrative-based psychoeducational intervention aimed to create a vivid cognitive experience of complex decision-making and modeled desirable behavioral changes through nurse-led, interactive video sessions using model patients. The control group received 4 nurse-led sessions comprising education about AMI and care seeking delivered using a didactic approach. Main Outcomes and Measures The primary outcome was the behavioral intention between the 2 groups, reflected by participants’ attitudes and beliefs about care seeking for AMI measured using the Acute Coronary Syndrome Response Index—Chinese version. The secondary outcome was AMI knowledge. Results Six hundred and eight participants (mean [SD] age, 67.2 [8.3] years; 469 [77.1%] male) were randomized to either the narrative-based psychoeducation group (n = 304) or the didactic education group (n = 304). The psychoeducational intervention group reported greater positive changes than the control group in their attitudes (β = −1.053 [95% CI, −1.714 to −0.391]; P &amp;amp;lt; .001) and beliefs (β = −0.686 [95% CI, −1.354 to −0.180]; P = .04) toward care seeking at the 3-month follow-up, and the difference was sustained at 12 months for both attitudes (β = −0.797 [95% CI, −1.477 to −0.117]; P = .02) and beliefs (β = −0.692 [95% CI, −1.309 to −0.012]; P = .047). There were no significant differences in AMI knowledge between the 2 study groups at the 3-month and 12-month time points. Conclusions and Relevance The results of this randomized clinical trial found that a novel approach of narrative-based psychoeducation was effective in improving patients’ behavioral intention to seek care for AMI symptoms. Longer-term follow-up to evaluate actual care-seeking behavior and clinical outcomes in patients with AMI is warranted to determine the sustained effects of this intervention. Trial Registration ChiCTR Identifier: ChiCTR-IIC-17010576
Low Risk of Neurodevelopmental Impairment in the COVID-19 Generation Should Not Make Researchers Complacent
Authors: Andréane Lavallée, Dani Dumitriu
Journal: JAMA Network Open (2022)

Kamran Hessami, MD; Amir Hossein Norooznezhad, MD; Sonia Monteiro, MD; Enrico R. Barrozo, PhD; Abolfazl Shirdel Abdolmaleki, MD, MPH; Sara E. Arian, MD; Nikan Zargarzadeh, MD; Lara S. Shekerdemian, MD; Kjersti M. Aagaard, MD, PhD; Alireza A. Shamshirsaz, MD
Assessment of Spending for Patients Initiating Dialysis Care
Authors: Riley J. League, Paul Eliason, Ryan C. McDevitt, James W. Roberts, Heather Wong
Journal: JAMA Network Open (2022)

Despite a widespread belief that private insurers spend large amounts on health care for enrollees receiving dialysis, data limitations over the past decade have precluded a comprehensive analysis of the topic.To examine the amount and types of increases in health care spending for privately insured patients associated with initiating dialysis care.A cohort study covering calendar years 2012 to 2019 included patients with kidney failure who had employer-sponsored insurance for 12 months following dialysis initiation. Data analysis was performed from August 27, 2021, to August 18, 2022. The data cover the entirety of the US and were obtained from the Health Care Cost Institute. The data include all medical claims for enrollees in employer-sponsored health insurance plans offered by multiple major health care insurers within the US. Participants included patients younger than 65 years who were continuously enrolled in these plans in the 12 months before and after their first claim for dialysis care. Patients also had to have nonmissing documented key characteristics, such as sex, race and ethnicity, and health characteristics.A claim for dialysis care.Out-of-pocket, inpatient, outpatient, physician services, prescription medication, and total health care spending. The hypothesis tested was formulated before data collection.The sample included 309 800 enrollee-months, which was a balanced panel of 25 months for 12 392 enrollees. At baseline, 7534 patients (61%) were male, 5415 (44%) were aged 55 to 64 years, and patients had been enrolled with their insurer for a mean of 30 months (95% CI, 29.9-30.1 months). In the 12 months before initiating dialysis care, total monthly health care spending was $5025 per patient per month (95% CI, $4945-$5106). Dialysis care initiation was associated with an increase in total monthly spending of $14 685 (95% CI, $14 413-$14 957). This increase occurred across all spending categories (dialysis, nondialysis outpatient, inpatient, physician services, and prescription drugs). Monthly patient out-of-pocket spending increased by $170 (95% CI, $162-$178). These spending increases occurred abruptly, beginning about 2 months before dialysis initiation, and remained increased for the subsequent 12 months.In this cohort study, evidence that private insurers experience significant, sustained increases in spending when patients initiated dialysis was noted. The findings suggest that proposed policies aimed at limiting the amount dialysis facilities charge private insurers and the enrollees has the potential to reduce health care spending in this high-cost population.
Reliability and Validity of an Instrument of COVID-19 Patient-Reported Symptoms in Outpatients
Authors: Diana Rofail, Pip Griffiths, Giulio Flore, Mohamed Hussein, Sumathi Sivapalasingam, Anna J. Podolanczuk, Ana Maria Rodriguez, Vera Mastey, Chad Gwaltney
Journal: JAMA Network Open (2022)

Importance Patient-reported outcome instruments are key in assessing COVID-19–related symptoms and associated burden. However, a valid and reliable instrument to assess symptom severity and progression among outpatients with COVID-19 is not yet available. Objectives To assess the extent to which the Symptoms Evolution of COVID-19 (SE-C19) instrument is valid, reliable, and able to detect symptom changes in outpatients with COVID-19, as well as to establish a definition of symptom resolution. Design, Setting, and Participants In this diagnostic/prognostic study, psychometric properties of SE-C19 were assessed in participants recruited into an ongoing, adaptive, phase 1/2/3, randomized, double-blind, placebo-controlled clinical trial, during 2020 to 2022. Adult outpatients with symptomatic COVID-19 were randomized 1:1:1 to receive 2.4 g or 8.0 g intravenous casirivimab and imdevimab or placebo, in outpatient centers at 114 sites, from 2 countries (US and Mexico). Main Outcomes and Measures Reliability, validity, and sensitivity to change of the SE-C19 were assessed. SE-C19 and Patient Global Impression of Severity (PGIS) were administered daily from predose at day 1 to day 29. Results Analysis was conducted on 657 adult outpatients (342 female patients [52.1%], 562 White patients [85.5%]), and 337 non-Hispanic patients [51.3%]. At baseline, patients reported a mean (SD) of 6.6 (3.9) symptoms (ie, rated as at least mild ) with a mean (SD) of 3.8 (3.3) of these symptoms being rated as moderate or severe. Stable patients according to PGIS showed scores with intraclass correlation values indicating moderate-to-good test-retest reliability (ie, 0.50-0.90). At baseline, 20 item scores (87%) varied significantly across PGIS-defined groups, supporting the validity of the SE-C19. A symptom-resolution end point was defined after excluding the item sneezing due to its low ability to discriminate severity levels, and excluding confusion, rash, and vomiting, due to their low prevalence in this population. Symptom resolution required complete absence of all remaining items, except cough, fatigue, and headache, which could be mild or moderate in severity. A total of 19 of 23 items from the SE-C19 instrument were identified as valid and reliable to measure disease-related symptoms in outpatients with COVID-19. Conclusions and Relevance This study identified 19 items that are valid and reliable to measure disease-related symptoms in outpatients with COVID-19, and proposed a definition of symptom resolution for potential use in future clinical trials.
Analysis of Emergency Department Encounters Among High Users of Health Care and Social Service Systems Before and During the COVID-19 Pandemic
Authors: Melanie Molina, Jennifer Evans, Juan Carlos Montoy, Caroline Cawley, Dave Graham-Squire, Kenneth Perez, Maria Raven, Hemal K. Kanzaria
Journal: JAMA Network Open (2022)

Although the general US population had fewer emergency department (ED) visits during the COVID-19 pandemic, patterns of use among high users are unknown.To examine natural trends in ED visits among high users of health and social services during an extended period and assess whether these trends differed during COVID-19.This retrospective cohort study combined data from 9 unique cohorts, 1 for each fiscal year (July 1 to June 30) from 2012 to 2021, and used mixed-effects, negative binomial regression to model ED visits over time and assess ED use among the top 5% of high users of multiple systems during COVID-19. Data were obtained from the Coordinated Care Management System, a San Francisco Department of Public Health platform that integrates medical and social information with service use.Fiscal year 2020 was defined as the COVID-19 year.Measured variables were age, gender, language, race and ethnicity, homelessness, insurance status, jail health encounters, mental health and substance use diagnoses, and mortality. The main outcome was annual mean ED visit counts. Incidence rate ratios (IRRs) were used to describe changes in ED visit rates both over time and in COVID-19 vs non-COVID-19 years.Of the 8967 participants, 3289 (36.7%) identified as White, 3005 (33.5%) as Black, and 1513 (16.9%) as Latinx; and 7932 (88.5%) preferred English. The mean (SD) age was 46.7 (14.2) years, 6071 (67.7%) identified as men, and 7042 (78.5%) had experienced homelessness. A statistically significant decrease was found in annual mean ED visits among high users for every year of follow-up until year 8, with the largest decrease occurring in the first year of follow-up (IRR, 0.41; 95% CI, 0.40-0.43). However, during the pandemic, ED visits decreased 25% beyond the mean reduction seen in prepandemic years (IRR, 0.75; 95% CI, 0.72-0.79).In this study, multiple cohorts of the top 5% of high users of multiple health care systems in San Francisco had sustained annual decreases in ED visits from 2012 to 2021, with significantly greater decreases during COVID-19. Further research is needed to elucidate pandemic-specific factors associated with these findings and understand how this change in use was associated with health outcomes.
Kinetics of Humoral Immunodeficiency With Bispecific Antibody Therapy in Relapsed Refractory Multiple Myeloma
Authors: Lindsay R. Hammons, Aniko Szabo, Abhishek Janardan, Binod Dhakal, Saurabh Chhabra, Anita D’Souza, Meera Mohan
Journal: JAMA Network Open (2022)

This case series describes the kinetics of humoral deficiency in patients with relapsed refractory multiple myeloma treated with bispecific antibodies, the infectious complications, and response to COVID-19 immunization.